tbuckley/cabot-search huggingface dataset:
Abstract 15727: Cancer and Atherosclerosis Share Numerous Pathogenic Drivers Representing Novel Translational Targets for Mutual Benefit
Authors: Richard Baylis, Hua Gao, Fudi Wang, Caitlin Bell, Lingfeng Luo, Jeanette Erdmann, Johan Bjorkegren, Derek Klarin, Nick J Leeper
Journal: Circulation (2022)

Cancer and cardiovascular disease make up nearly half of all deaths in the United States. Despite knowing a great deal about each of these diseases individually, surprisingly little is known about how these diseases interact within patients or the common dysregulated genes and pathways that these diseases share. These diseases are known to share numerous risk factors and emerging epidemiologic data suggests that the presence of coronary artery disease (CAD) increases the risk of developing cancer. In addition, studies like the CANTOS trial have shown that targeting mutually detrimental pathways could yield benefit for both diseases. To understand the relationship of cancer and CAD, we tested two hypotheses, 1) the similarities between cancer and CAD are explained, in part, by shared genetic factors and 2) these diseases share dysregulated processes/pathogenic drivers and that targeting these processes could result in mutual clinical benefit. To test these hypotheses, we assessed the genetic correlation of CAD and each cancer subtype in the UK biobank. This identified a surprising genetic overlap between prostate cancer and CAD. However, the other cancers lacked significant genetic correlation with CAD, suggesting that common genetic factors were unlikely to be mediating their interaction. To identify common pathogenic drivers, we used transcriptomic data that had been correlated with either cancer survival or CAD disease severity/outcomes to generate transcriptional risk profiles for each disease. We then intersected these data to identify mutually detrimental processes, which included several known pathways including inflammation and hypoxia but also numerous novel pathways. Interestingly, we found that many cancers were indistinguishable from CAD based on their transcriptomic risk profile. Next, we used the drug prediction algorithm, OCTAD, to identify novel drug targets for each disease state and then validated our predictions using a pharmacovigilance approach with EMR data. Taken together, our study suggests that the interaction of cancer and CAD is primarily driven by shared pathogenic drivers rather than shared genetic predisposition and that targeting these processes may allow for mutual clinical benefit.
Abstract 15863: Impact of Right and Left Ventricular Dysfunction on Mortality in Secondary Mitral Regurgitation Patients Without Surgical and Interventional Treatment
Authors: Dan Liu, kai hu, Kolja Lau, Jonas Müntze, Octavian Maniuc, Peter Nordbeck
Journal: Circulation (2022)

Introduction: Secondary mitral regurgitation (SMR) is related with poor clinical outcome. Impact of right ventricular (RV) dysfunction with or without left ventricular (LV) dysfunction in SMR patients remains unclear. Hypothesis: This study aimed to investigate the prevalence of isolated LV, RV, and biventricular dysfunction, and to determine their prognostic implication in moderate-to-severe SMR without surgical and interventional treatment. Methods: A total of 1090 consecutive moderate-to-severe SMR patients without surgical and interventional treatment hospitalized in our hospital center between 2009 and 2018 (aged 75±12years, 60.4% male) were included. Clinical and echocardiographic characteristics were analyzed. All patients completed at least 1-year clinical follow-up. The primary endpoint was defined as all-cause death. Results: Mean left ventricular ejection fraction (LVEF) was 44.6±16.2%, and 59.3% of patients had LVEF &lt;50% (defined as LV dysfunction). RV dysfunction was defined as a reduced tricuspid annular plane excursion (TAPSE&lt;17mm) or an increased systolic pulmonary artery disease (sPAP&gt;40mmHg). All-cause mortality was 47.8% [follow-up period: median 23 (8-40) months]. Patients were divided into 4 subgroups: 1) preserved biventricular function: n=136 (12.5%); 2) isolated LV dysfunction: n=97 (8.9%); 3) isolated RV dysfunction: n=308 (28.3%); 4) biventricular dysfunction: n=549 (50.4%). The mortality in above groups was 27.2%, 36.1%, 50.0% and 53.7%, respectively. Multivariable survival analysis showed that isolated LV dysfunction, isolated RV dysfunction, or biventricular dysfunction were all independently associated with increased all-cause mortality, after adjustment for age, sex and other clinical covariates associated with mortality. Conclusions: Compared to patients with preserved biventricular function or isolated LV dysfunction, RV and biventricular dysfunction are associated with significantly higher all-cause mortality in SMR patients without surgical/interventional treatment. This might constitute important implications for planning and timing of therapy.
Abstract 15536: Surface Lin28a Expression Consistent With Cellular Stress Parallels Indicators Of Senescence
Authors: Kathleen M Broughton, Carolina Esquer, Oscar H Echeagaray, Fareheh Firouzi, Grant Shain, David Ebeid, Megan M Monsanto, Dena Yaareb, Leila Golgolab, Natalie A Gude, Mark A Sussman
Journal: Circulation (2022)

Aims: Declining cellular functional capacity resulting from stress or aging is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and aging responses. Altered localization of the RNA binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Surface Lin28A redistribution is indicative of oxidative stress response in CIC associated with aging and senescence. Methods and Results: Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated senescence marker p16 and beta-galactosidase (β-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single cell RNASeq reveals upregulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300uM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and β-gal with predominantly diploid content. Conclusion and Clinical Perspective: Surface Lin28A is identified as novel surface marker of oxidative stress conditions that cause DNA damage and cellular senescence. Accumulation of surface Lin28A was inhibited by antioxidant treatment with lowered indices of cellular stress and senescence, revealing the potential of surface Lin28A as a diagnostic stress marker. Therapeutic strategies targeted toward surface Lin28 expression set the stage for next generation senolytics to remove stressed or senescent cells and promote recovery from tissue injury or aging.
Abstract 217: Association Of Ventricular Fibrillation Instantaneous Amplitude At Time Of Defibrillation With Resuscitation Outcome
Authors: Xabier Jaureguibeitia, Heemun Kwok, Jason Coult, Jennifer E Blackwood, Peter J Kudenchuk, Thomas Rea
Journal: Circulation (2022)

Introduction: Quantitative measures of the ventricular fibrillation (VF) ECG waveform predict defibrillation outcomes. A prior study observed that greater Instantaneous Amplitude (IA) of the VF ECG, measured at the instant of defibrillation (Figure), predicted better outcome independent of other VF measures. If true, resuscitation might be improved by synchronizing shock to ECG amplitude. We sought to determine whether IA was an independent predictor of shock-specific outcome using a larger independent dataset. Methods: We investigated adult out-of-hospital VF cardiac arrest cases in a metropolitan EMS system treated with a Philips MRx defibrillator. For each shock, we computed the IA as the absolute value of the ECG at the time of shock delivery. We also computed the amplitude spectrum area (AMSA), a well-characterized waveform measure, from the 3-second CPR-free period preceding the shock. Study outcome was return of spontaneous circulation (ROSC) after each shock. We used Wilcoxon test to evaluate the unadjusted relationship between IA and shock-specific ROSC, and a generalized linear mixed-effect (GLME) model to assess whether IA was associated with shock-specific ROSC independent of AMSA. Results: We included 1516 shocks from 567 patients, with a median (IQR) of 2 (1-3) shocks per patient and shock-specific ROSC rate of 22% (337/1516). IA was correlated with AMSA; Pearson’s R = 0.43. Median (IQR) IA was greater for shocks that resulted in ROSC, with IA of 0.14 (0.05-0.25) mV vs 0.09 (0.04-0.18) mV, (p&lt;0.001). However, when both IA and AMSA were included in a GLME model, AMSA was significantly associated with ROSC (OR 2.09, 95% CI 1.74-2.50 for an IQR change in AMSA) but IA was not (OR 1.04, 95% CI 0.92-1.18 for an IQR change in IA). Conclusions: IA did not independently predict ROSC after controlling for AMSA. Thus, IA is likely a surrogate for other waveform measures, limiting its usefulness to guide instantaneous defibrillation timing as a means to improve outcome.
Abstract 15668: Concurrent ST Elevation Myocardial Infarction and Gastric Perforation: A Management Dilemma
Authors: Oluwaseun E Fashanu, Omofolarin Babayale, Garba Rimamskep Shamaki, Elizabeth Lee
Journal: Circulation (2022)

Case Presentation: A 62-year-old male with RBBB, hypertension, diabetes, and former tobacco use presented with nausea, vomiting, abdominal and chest pain which responded to Pepto-Bismol. Examination revealed tachycardia, hypertension, a rigid, tender abdomen with guarding and rebound. His ECG showed anterolateral STEMI with dynamic changes. Chest and abdomen CT revealed a perforated ulcer with free air and also noted a hypodense region of the LV in the vascular distribution of the LAD suggestive of an acute infarct. Echo revealed LAD territory wall motion abnormalities with an estimated LVEF of 35%. It was decided to proceed with coronary angiography first based a multidisciplinary team discussion between the patient, surgical, and cardiology team. This showed a totally occluded proximal LAD, felt to be the culprit lesion, 90% proximal stenosis of LCx, and diffuse disease of RCA (figure). Right heart catheterization showed mixed shock. Plain old balloon angioplasty of LAD was done, IABP placed, and pressors started. He then had an exploratory laparotomy with lysis of adhesions and Graham patch repair of perforated gastric ulcer. He ultimately had a DES to his LAD 15 days after tolerating DAPT. Repeat Echo done after 2 months of GDMT revealed a recovered LVEF of 55%. Discussion: STEMI and perforated viscus are two clinical emergencies with high mortality. Few case reports of simultaneous occurrence are documented in the literature with no guideline-directed management given the rarity of its presentation. In our patient, we preceded with coronary angiogram to attain moderate hemodynamic stability with POBA aiding in revascularization and IABP providing mechanical support. Furthermore, early revascularization in STEMI is known to have mortality benefits. Our approach led to a favorable outcome with resultant recovery in cardiac performance and can be considered as a strategy to tackle similar presentations with expert deliberation.
Abstract 208: Patient And Event Characteristics Associated With Duration Of Resuscitation In Children Undergoing In-hospital Cpr
Authors: Amanda O'Halloran, Ryan W Morgan, Kevin Kennedy, Robert A Berg, Cody-Aaron Gathers, Maryam Naim, Vinay M Nadkarni, Ron Reeder, Alexis A Topjian, Monica E Kleinman, Heather A Wolfe, Paul S Chan, Robert M Sutton
Journal: Circulation (2022)

Introduction: Duration of cardiopulmonary resuscitation (CPR) in patients without return of spontaneous circulation (ROSC) is a proxy measure for the persistence of intense resuscitation efforts. We evaluated the association between patient and event characteristics and resuscitation duration among children who did not survive a CPR event. Methods: Retrospective cohort study using the American Heart Association’s Get With The Guidelines ® -Resuscitation registry. Pediatric CPR events without ROSC (non-survivors) from 2000-2021 were included. Multivariable hierarchical logistic regression evaluated which patient and event characteristics with a bivariate association (p&lt;0.05) were associated with CPR duration among non-survivors. Results: Of 13,899 eligible pediatric CPR events, 3850 did not have ROSC and comprised the primary cohort. Median CPR duration was 28 min (IQR: 16-46 min). After multivariable adjustment, several patient and event characteristics were associated with CPR duration. CPR duration was briefer by: age group (neonates compared to older children [-4.9 min, 95% CI: -8.9 to -0.9 min, p=0.02]); need for mechanical ventilation (-7.6 min [95% CI: -10.3 to -4.9 min, p&lt;0.001); and event location: ED vs. PICU (-4.0 min [95% CI: -7.5 to -0.6 min], p=0.02). CPR duration was longer by initial event rhythm as compared with asystole: bradycardia (8.4 min [95% CI: 5.7 to 11.0 min], p&lt;0.001); PEA (8.2 min [95% CI: 5.7 to 11.0 min), p&lt;0.001), and pulseless VT (6.2 min [95% CI: 0.1 to 12.3 min], p=0.047). CPR duration was similar by sex and race. Conclusions: Several factors including age, rhythm, and event location are associated with resuscitation duration in pediatric patients requiring CPR but there were no sex or racial differences. Further investigation is needed to determine current practices regarding termination of resuscitation and to generate guidelines for this complex decision-making.
Abstract 15824: Microvascular Endothelial Kir2.1 Channels Play Important Role in Flow-Induced Dilation During Hypertension in Humans
Authors: Natalia Do Couto, Sang Joon Ahn, Ibra Fancher, Shane A Phillips, Irena Levitan
Journal: Circulation (2022)

Hypertension is associated with decreased endothelial function through reduced contributions of NO. Our recent study discovered that flow-induced generation of NO in resistance arteries of mice and humans, and flow-induced vasodilation (FIV), a hallmark of the endothelial response to flow, critically depend on endothelial inwardly-rectifying K+ channels (Kir2.1). The goal of this study was to establish whether these channels contribute to the impairment of endothelial function in peripheral resistance arteries of humans with hypertension. We measured microvascular function in vessels extracted from subcutaneous fat biopsies isolated from 28 subjects: normotensive (n=19; 30.6±4.4yo; systolic blood pressure-SBP: 115.2±5.7mmHg; diastolic blood pressure-DBP: 75.3±11.3mmHg) and hypertensive (n=9; 50±5.2yo; SBP: 147.1±6.1 mmHg; DBP: 93.1±16.8mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive subjects as demonstrated by a significant reduction in dilation when compared to the normotensive group. Furthermore, our data suggest that the impairment of FIV in this cohort can be partially attributed to a Kir-dependent vasodilation. Specifically, we show that blocking Kir channels with a specific inhibitor, ML133, or functionally downregulating with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in significant decrease in FIV in normotensive subjects and smaller effect in hypertensive patients. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP indicating that Kir contribution reduces as blood pressure increases. In addition, we show that exposing normotensive vessels to acute high pressure, which is known to impair FIV, results in loss of Kir channel contribution, as high-pressure impairs vasodilation in normotensive vessels but no effect is seen when these vessels were incubated with dnKir2.1. Overexpressing WTKir2.1 in endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive patients. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.
Abstract 15671: Targeting Chromatin Structure: The Combined Inhibition of Histone Deacetylases and Bromodomain Proteins in Normalizing Persistently Activated Pulmonary Hypertensive Fibroblasts
Authors: Hui Zhang, Min Li, Cheng-Jun Hu, Kurt R Stenmark
Journal: Circulation (2022)

Rationale: The multifactorial nature of pulmonary hypertension (PH) suggests epigenetic changes as potential determinants of vascular remodeling through regulating gene expression (both up-regulated and down-regulated genes) in vascular cells. Changes in the chromatin state (especially histone acetylation) of specific genes can lead to their repression or activation. We and others have demonstrated histone deacetylases inhibitors (HDACi) and histone acetylation readers inhibitors (BRDi) can prevent and ameliorate PH changes by normalizing pathological gene expression. However, the non-histone protein targets and the narrow therapeutic window of currently available HDACi limits their clinical utility. In this study, we evaluated the effect of combination treatments using a new HDACi (OKI-005, US patent) with high potency and selectivity for HDACs (targeting decreased genes) together with BRDi (targeting increased genes), in low doses. Methods and Results: Cultured human pulmonary artery fibroblasts derived from patients with IPAH (PH-Fibs) or from control donors (CO-Fibs) were used as in vitro model system. PH-Fibs exhibit increased pro-inflammatory genes (e.g. CXCL12), proliferation markers (e.g. Mki67) and anti-apoptosis genes (e.g. BCL2) as well as decreased anti-inflammatory genes (e.g. HMOX1), anti-proliferation genes (e.g. P21) and pro-apoptotic genes (e.g. PERP). In PH-Fibs, the increased expressed CXCL2 gene exhibited more opened chromatin structure and BRD4 binding (ChIP-assay), and BRDi (JQ1) can decrease its expression in a dose dependent trend. At the low doses, JQ1 (100 nM) alone is sufficient to normalize most of increased genes, while the new HDACi (OKI-005) was more effective in normalizing decreased genes in PH- Fibs. The combination of low dose of JQ1 (100 nM) and OKI-005 (64 nM) was sufficient to normalize both increased genes and decreased genes thus inhibiting the persistently activated PH-phenotype without deleterious effects on CO-Fibs. Conclusion: Combination of HDACi and BRDi in low doses is effective in normalizing the persistent activation of PH-Fibs without deleterious effects on control cells, offering promise for epigenetic-targeted therapies in PH.
Abstract 232: The Association Between Amplitude Spectrum Area And An Automated External Defibrillator Algorithm’s Detection Of Ventricular Fibrillation During Cardiopulmonary Resuscitation
Authors: Kevin Burgett, Chenguang Liu, Stacy Gehman, Dawn Jorgenson
Journal: Circulation (2022)

Introduction: Prior studies have reported the performance of a Philips analysis-through-CPR (ATC) shock determination algorithm during chest compressions (CCs). Amplitude spectrum area (AMSA), calculated for ventricular fibrillation (VF) rhythms, has also been reported as a predictor of defibrillation success. This study evaluated how AMSA scores for VF rhythms are associated with the performance of the shock determination ATC algorithm. Methods: A total of 838 VF rhythms were extracted from 304 adult patients recorded by Philips FR3 AEDs and Philips MRx defibrillators from multiple Emergency Medical Service (EMS) systems. Each extracted VF rhythm contained at least 11 seconds (s) of data recorded during CCs, followed by at least 2 s of CPR-free ECG data used to retrospectively calculate an AMSA score for the rhythm before the onset of a shock. VF rhythms were split into three groups according to their AMSA score: Low (&lt;6 mV*Hz), Medium (6-15 mV*Hz), High (&gt;15 mV*Hz). We evaluated the sensitivity of the ATC algorithm during CCs for each AMSA range. Results: During the 11s period with active CCs, 77.8% (Table 1) of all VF rhythms were identified by the ATC algorithm. The remaining unidentified VF rhythms (22.2%) would require a pause in CPR for a hands-off analysis. The median AMSA score for identified VF rhythms was significantly greater than the unidentified VF rhythms (7.8 vs. 6.1 [mV*Hz], p &lt; .001). The sensitivities during CCs for VF rhythms in the Low, Medium, and High AMSA score ranges were 66.4%, 82.6%, and 88.1%, respectively. Conclusions: The present study has shown the association between Philips ATC algorithm’s sensitivity of identifying VF during CCs and the corresponding AMSA score. Such results suggest that when the ATC algorithm identifies a shockable rhythm during CCs, this rhythm’s AMSA score is likely to be high resulting in a higher likelihood of shock success.
Abstract 174: Usefulness Of Cerebrospinalfluid Partial Pressure Of Carbone Dioxide As A Predictor Of Poor Neurological Outcomes In Cardiac Arrest Patients Who Underwent Target Temperature Management.
Authors: SOYOUNG JEON, Hong Joon Ahn, Jung Soo Park, Yeonho You, Insool Yoo, Seung Whan Kim, Jinwoong Lee, Seung Ryu, Wonjoon Jeong, Yongchul Cho, Changshin Kang
Journal: Circulation (2022)

Aim: We aimed to predict the six-month neurological outcomes of out-of-hospital cardiac arrest(OHCA) patients who underwent target temperature management(TTM) using cerebrospinal fluid(CSF) partial pressure of carbon dioxide(PCO 2 ). Hypothesis: We hypothesized that CSF PCO 2 would decrease after cardiac arrest. The buffer system and viscosity of the CSF change when the blood-brain barrier ​​and blood cerebrospinal fluid barrier are disrupted and ions and proteins are released from damaged neurons and cells into the CSF. Methods: We performed gas analysis of arterial blood and CSF samples to assess the PCO 2 of OHCA patients who underwent TTM from November 2018 to August 2021. The PCO 2 was assessed immediately (Day 0) and 24h (Day 1), 48h (Day 2), and 72h (Day 3) after the return of spontaneous circulation (ROSC). The primary outcome was Cerebral Performance Category 3-5 six months after cardiac arrest. Results: Of 67 (males, 49; 73.1%) enrolled patients, thirty-nine(58.2%) had a poor neurologic outcome. The poor neurologic outcome group had significantly lower CSF PCO 2 each time after ROSC (Figure 1). The area under the curve of the CSF PCO 2 on Day 1 was 0.823 (95% confidence interval [CI], 0.692-0.915), with a cutoff value of 30 mmHg. Conclusion: The CSF PCO 2 was lower at each time point after the ROSC for the patients with poor neurologic outcomes, and it maybe a useful predictor of neurologic outcomes of OHCA survivors treated with TTM.